The combination of selective inhibition of the cannabinoid CB1 receptor and activation of the cannabinoid CB2 receptor yields improved attenuation of motor and autonomic deficits in a mouse model of spinal cord injury.

Abstract

Spinal cord injury (SCI) is a tremendous public health problem in the United States and worldwide. The Centers for Disease Control and Prevention and the University of Alabama National Spinal Cord Injury Statistical Center estimate the annual incidence of SCI in the United States is between 11,000 and 12,000 injured per year.14,31 There are approximately 250,000 people in the United States living with disability related to an SCI.14,31 The cost of SCI to society is considerable, with a monetary estimate of more than $9,700,000,000 per year.14 Considering that more than half of individuals affected by SCI are young males between the ages of 15 and 29 years, the cost to society from loss of productivity may even be greater. Internationally, the incidence of SCI is increasing at an alarming rate, as motorization and in many regions violence increases. Although there have been advances in the care and rehabilitation of patients with SCI, currently there are unfortunately very few, if any, medical treatments for acute SCI that effect functional outcome.3,17,22 The current mainstay in medical therapy for acute injury is high-dose methylprednisolone.3,10–12,22,25 Many experts, however, believe that the risk of adverse events associated with high-dose steroids may outweigh the potential benefits gained through its use.22,25 According to Hurlbert, the continued use of steroids in acute SCI is “primarily out of peer pressure and fear of litigation.”22 Just as in traumatic brain injury, a complex array of secondary insults is responsible for ongoing neuronal damage after SCI.3,28 Neuroprotection is defined by Anderberg et al.3 as measures to “counteract secondary injury mechanisms and/or limit the extent of damage caused by self-destructive cellular and tissue processes.” Neuroprotective medications may be able to interrupt this destructive progression and theoretically have the potential to yield improved functional recovery.3 The search for neuroprotective agents that demonstrate efficacy in SCI is of paramount importance given the increasing incidence and devastating nature of the disease. Recently there has been an explosion of interest in the use of cannabinoids in treatment of central nervous system (CNS) diseases.2,4,8,13,15,18,20,32,34,36–38 Croxford15 identified multiple sclerosis, Parkinson’s disease, neuroprotection, analgesia, emesis, and anorexia and obesity all as areas with potential for the clinical application of cannabinoids. Our group has been exploring the role of cannabinoid receptor modulation in murine models of several CNS disorders such as stroke, multiple sclerosis, traumatic brain injury, and SCI.30,37,38 The term cannabinoid refers to any natural or synthetic compounds that resemble in structure and/or function those found naturally in the plant Cannabis sativa. Two types of cannabinoid receptors in the mammalian endocannabinoid system have been identified to date. The CB1 and CB2 receptors both work through Gi protein–coupled mechanisms on adenylyl cyclase function, as well as through other mechanisms.1,13,15,32 The CB1 receptor is found throughout the CNS and peripheral nervous system where it is localized to axon terminals.1,2 Activation leads to inhibition of neurotransmitter release and therefore works via presynaptic inhibition of neurotransmission. The CB1 receptor is constitutively active and subject to endogenous tone by circulating endocannabinoids. The receptor has been shown to participate in control Copyright © 2009 by The Congress of Neurological Surgeons 0148-703/09/5601-0084